Anti-infective and antithrombogenic medical articles and method for their preparation

ABSTRACT

An anti-infective medical article has chlorhexidine bulk distributed throughout a polyurethane base layer and may have a coating layer on the base layer. The coating layer may be chlorhexidine, an antibiotic, or an antithrombogenic agent permeated into the surface or it may be a polymeric surface layer having bulk distributed chlorhexidine laminated onto the base layer. The invention includes a method for preparing the article wherein a homogeneous melt of polymer and chlorhexidine is prepared by twin screw compounding and the melt is extruded to give a medical article having bulk distributed chlorhexidine. The article may then be laminated by dipping into a solution of chlorhexidine and a substantially hydrophilic polymer in a solvent.

This application is a continuation-in-part of application Ser. No.317,418, filed Mar. 1, 1989, abandoned, which is a continuation-in-partof copending application Ser. No. 298,392, filed on Jan. 18, 1989, abn.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to medical articles, and, more particularly,relates to articles which inhibit or reduce bacterial growth and thedevelopment of thrombi in a living body during their use and to theirpreparation.

2. Background of the Invention

Plastic medical articles intended for insertion into a patient must havea smooth surface to minimize patient discomfort. Another desirablefeature of such articles is some means to control infection, which is afrequent complication during use of medical articles which come intocontact with a body tissue or fluid. For example, infection remains alethal complication of vascular prosthetic grafting. Catheters used forvascular access, both arterial and venous, abdominal cavity tubing,drainage bags, and various connectors are common sources of infection.In particular, a high percentage of patients who require long-termurinary catheters develop chronic urinary tract infections, frequentlyin conjunction with episodes of fever, chills, and flank pain. Suchpatients are at risk of developing bacteremia or chronic pyelonephritis,conditions of high morbidity and mortality.

Medical articles are frequently fabricated from polyurethane by moldingand extruding techniques. A frequent problem, particularly duringextrusion, is the difficulty of obtaining homogeneous melts free of gelparticles which adversely affect the smoothness of the surface of theextruded product. A discussion of these problems is given in U.S. Pat.No. 4,371,684 to Quiring et al.

Many attempts to solve the problem of infection have been directedtoward adherence of an antibacterial agent to the plastic article. Gouldet al., in U.S. Pat. No. 3,695,921, discloses a catheter coated with alayer of hydrophilic polymer having an antibiotic absorbed therein.

EP published application 229,862 teaches thermoplastic polyurethanemedical devices having an antimicrobial agent on its surface.

Fox et al. in U.S. Pat. No. 4,581,028, teaches infection resistantplastic medical articles, such as vascular grafts, having incorporatedantimicrobial agents, such as silver sulfadiazine and pipericillin. Thearticles are prepared by dipping procedures.

Mustacich et al., in U.S. Pat. No. 4,479,795, discloses medical devicesof permeable polymers including a releasably incorporated coating of acarboxylate antimicrobial agent which diffuses to the surface of thedevice to form an antimicrobial barrier.

In Japanese Patent Application No. SHO 60-36064 a polyurethane orsilicone catheter is dipped into an aqueous solution of chlorhexidine toabsorb the chlorhexidine into the polymer. The chlorhexidine is thenconverted to a water insoluble form by dipping into a solution of anacid. Japanese Patent No. 59,228,856 discloses an elastomeric catheterhaving a water insoluble biguanide or salt thereof incorporated as athin coating membrane in the surface of the catheter.

PCT published application No. WO 86/02561 teaches a medical device of ahydrophobic thermoplastic polymer having up to 1% chlorhexidine basecoated thereon or incorporated therein.

UK Patent Application No. 2,084,466A discloses a polypropylene articlerendered biocidal with chlorhexidine base, and suggests that the articlemay be prepared from other plastics.

Solomon et al., in U.S. Pat. No. 4,713,402, discloses a method forattachment of a quaternary salt to the surface of a polymeric articleand affixation of an antibiotic or antithrombogenic agent to the salt.

In U.S. Pat. Nos. 4,521,564 and 4,642,242, Solomon et al. discloses apolyurethane article having an antithrombogenic agent covalently bondedto an amine group in the article surface.

McGary et al., in U.S. Pat. No. 4,678,660, discloses a polyurethanearticle having coated thereon a layer of polyurethane alloy containing adispersed complex of a quaternary salt with either an antithrombogenicagent or an antibiotic.

Although all of the above disclosures have addressed the problems ofinfection and thrombogenesis during use of medical articles,satisfactory solutions have not yet been disclosed, particularly formedical articles, such as catheters, to be introduced and advancedthrough body passages. The present invention is directed towardproviding a solution.

SUMMARY OF THE INVENTION

A method for preparing an anti infective medical article includespreparing a homogeneous melt of a substantially hydrophilic polymer andan anti-infective agent and extruding the melt through a die to form amedical article having the anti infective agent distributedsubstantially evenly throughout the bulk of the polymer (hereinafterreferred to as bulk distributed). The term anti infective agent isherein intended to mean any agent which inhibits bacterial growth, andthus includes antibiotics, antibacterial agents, antiviral agents andantimicrobial agents. The extruded article may be steeped in a solutionof chlorhexidine to provide the article with additional chlorhexidine asa coating permeated into the surface of the article. The melt ispreferably prepared by blending polymer pellets and chlorhexidine untilan even coating of chlorhexidine on the polymer is obtained, followed byheating to give a homogeneous melt. Most preferably, polymer pellets andchlorhexidine powder are simultaneously blended and melted by twin screwcompounding to form the homogeneous melt. The melt may then be extrudedfrom the compounder and chipped.

In another embodiment of the method of the invention, two polymer meltsare prepared, at least one of which contains bulk distributedchlorhexidine. The two melts may then be coextruded to give a laminatedarticle having chlorhexidine bulk distributed in at least one of thebase or laminating layers. Alternatively, an article may be laminated bydipping into a solution of a chlorhexidine salt and a thermoplasticpolyurethane in a solvent.

The invention includes a method to render the article having bulkdistributed chlorhexidine anti-thrombogenic by coating the article witha quaternary ammonium salt and reacting the coating of salt with anantithrombogenic agent.

Preferred polymers are siloxane-urethane copolymers, or, mostpreferably, polyurethanes and polyurethaneureas. The chlorhexidine maybe either in the form of the free base or, preferably in the form of asalt such as the hydrochloride, acetate and gluconate.

Another aspect of the invention is a medical article havingchlorhexidine base or a salt thereof bulk distributed throughout thearticle. The preferred article additionally has a layer ofchlorhexidine, preferably a chlorhexidine salt, permeated into thesurface of the article. Another embodiment of the article of theinvention is a laminated article having two polymeric layers, at leastone of which has chlorhexidine bulk distributed. Alternatively, thearticle having bulk distributed chlorhexidine may have a coating of ananti-infective or antithrombogenic agent on the base layer or on thelaminating layer. The preferred article of the invention is a tubing,most preferably a catheter.

Thus, the invention provides a method to prepare an anti-infectivearticle from a high melting hydrophilic polymer having mechanicalproperties providing advantages not afforded by hydrophobic polymers.The preferred article has a surface layer of chlorhexidine which israpidly released and bulk distributed chlorhexidine which is releasedslowly providing a long lasting anti infective effect.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a typical polymeric tubing of theinvention;

FIG. 2-5 are cross-sectional views of the tubing of FIG. 1 taken alongthe line 2--2 thereof showing various embodiments of the tubing afterapplication of chlorhexidine thereto;

FIG. 6 is a perspective view of a laminated tubing of the invention;

FIG. 7-9 are cross sectional views of the tubing of FIG. 6 taken alongthe line 7--7 thereof showing applied anti-infective agent; and

FIG. 10 is a cross-sectional view of a tubing covered by laminatedlayers containing chlorhexidine.

DETAILED DESCRIPTION

While this invention is satisfied by embodiments in many differentforms, there will herein be described in detail preferred embodiments ofthe invention, with the understanding that the present disclosure is tobe considered as exemplary of the principles of the invention and is notintended to limit the invention to the embodiments illustrated anddescribed. The scope of the invention will be measured by the appendedclaims and their equivalents.

In accordance with the present invention, a significant reduction ofinfection associated with the use of medical articles is achieved bycombining an anti-infective agent with the article. If theanti-infective agent can form a salt, the article of the invention iscontemplated to include the salt form of the agent as well as the parent(nonsalt) form. A variety of anti-infective agents as known in the artmay be used, including antibiotics such as penicillin and antibacterialagents such as silver sulfadiazine. In some cases, it may be desirableto provide dual anti-infective action with two or more agents. Theinvention will be described in terms of the preferred chlorhexidine, abiguanide of known safety and high activity against a wide variety oforganisms, including gram negative and gram positive bacteria andyeasts, with the understanding that the invention contemplates any antiinfective agent which may be bulk distributed in the polymer by themethod of the invention.

The medical article of the invention may be any medical articlecompatible with chlorhexidine which, absent the chlorhexidine, may leadto infection when in contact with a body tissue or fluid. Exemplary of,but not limited to, such articles are vascular access (arterial andvenous) catheters, introducers, vascular grafts, urinary catheters andassociated articles, such as drainage bags and connectors, and allabdominal cavity drainage tubing, bags and connectors. Preferredarticles are polymeric, most preferably a hydrophilic polymeric vascularaccess catheter.

Selection of a polymer to be used for catheter fabrication requires abalancing of several properties. First, the catheter must be stiffenough to be inserted into, for example, a blood stream, withoutkinking. However, once in contact with the blood, it should preferablysoften and become sufficiently flexible to bend and be advanced throughthe tortuous path of the vessel.

Polymers which exhibit suitable mechanical and hydrophilic behavior forfabrication of the catheter of the invention are, for example,substantially hydrophilic, polyurethanes, polyurethaneureas, andsiloxane-urethane block copolymers. Preferred polymers are polyurethanesor polyurethaneureas having a resin hardness of about 50 A to 75 D whenmeasured under standard room conditions of 23° C. and 50% relativehumidity, and a water absorption capacity of about 0.6 to 6.0%,preferably about 1.5 to 3.0% (all percentages given herein are by weightunless otherwise stated). Exemplary of suitable polymers and theirhardness and water absorption percentages are polyurethane 80 A (1.85%),polyurethane 55 D (1.66%), polyurethaneurea 70 A (1.94%), siliconeurethane copolymer 70 A (1.87%) and silicone-urethane copolymer 65 D(1.88%). Polyolefins in contrast are hydrophobic, absorbing about 0.04to 0.4% water, and are unsuitable for the present invention because, asshown in Example XV, they remain rigid, inflexible and unable to advancethrough winding blood vessels without kinking or rubbing against thevessel wall causing irritation, patient discomfort and possiblyphlebitis.

Various embodiments of the article having bulk distributed chlorhexidineare contemplated to fall within the scope of the invention. For example,the polymeric article may have a layer of chlorhexidine coated onto itssurface, or the chlorhexidine may be bulk distributed in the article. Apolymeric base layer, with or without bulk distributed chlorhexidine,may have one or more laminated layers of the same or another polymerthereon. Different properties may desirably be conferred on the articleby use of different polymers. The laminated layers may or may not havebulk distributed chlorhexidine. The layers may be of different thicknessand may have different concentrations of bulk distributed chlorhexidineor may have two or more different anti-infective agents. The preferredarticle of the invention has a layer of chlorhexidine coated onto thesurface of the article and bulk distributed chlorhexidine therein.

Articles of the invention having bulk distributed chlorhexidine may beprepared by extruding a melt of the polymer and chlorhexidine through adie. The chlorhexidine may be melted or may be a solid uniformlydistributed in the polymer melt. The melt to be extruded may containabout 0.05% to 10%, preferably about 1 to 5% by weight of chlorhexidine,and may be prepared in any suitable way. For example, the polymer andchlorhexidine may be melted, and the melts combined and mixedthoroughly. While blending of separate melts may be performed, thismethod is less preferred because the high viscosities of the melts makeuniform blending difficult resulting in an article having a roughsurface.

The preferred method for preparing the melt for extrusion is to blendthe polymer and chlorhexidine in particulate form prior to melting. Ingeneral, particulate blending may be carried out by any suitable mixingtechnique, such as stirring the polymer pellets and chlorhexidine powdertogether, or, preferably, by tumbling. This method is straightforwardand is the method of choice for preparation of melts of polyurethanesand chlorhexidine base. It has been found, however, that particulatechlorhexidine salts and polyurethane pellets do not form uniform blendsby these conventional procedures when the concentration of the salt isgreater than about 1% by weight. If the salt and pellets are notuniformly blended prior to melting, the melt and therefore the extrudedarticle will contain nonhomogeneously distributed salt and, as aconsequence, significant areas of rough surface having little or nosalt.

In order to prepare uniform blends of higher salt concentration, thepolymer pellets may first be surface wetted by thorough mixing of thepellets with about 0.1 to 2% by weight of a polyol. Any suitablepolyether or polyester polyol may be used, as, for example,polytetramethylene oxide (PTMO) having a molecular weight of about 500to 3,000. These products are well-known and are commercially available.

A preferred method for blending chlorhexidine salts uniformly withpolymer pellets is to melt and repellitize the ingredients with a twinscrew compounder. The polymer pellets, chlorhexidine salt and otheringredients such as fillers and pigments, may be fed to the compounderat a suitable rate. In the compounder, the ingredients are melted andblended and then extruded into strands. The strands may be pelletizedand dried prior to further processing. A corotating intermeshing twinscrew extruder may be used, such as Model ZDSK 28 from Werner andPfleiderer Corp., Ramsey, N.J.

The homogeneous pellets of polymer and chlorhexidine prepared asdescribed above may be remelted and molded or extruded into the desiredshape of the medical article. For the preferred catheter of theinvention, the melt may be extruded into tubing using conventionalequipment, such as, for example, a Killion extruder with a one inchdiameter barrel and a 24:1 (1/d) screw.

The temperature processing range for uniform blends of particulatechlorhexidine and polymer depend on the polymer being extruded. Ingeneral, melting and extrusion may be performed over a temperature rangeof about 160° to 250° C., preferably about 200°-235° C.

The article of the invention having bulk distributed chlorhexidine maybe steeped in a solvent solution of chlorhexidine to permeate a layer ofchlorhexidine into the surface of the article. An effective coating ofchlorhexidine may be obtained when the steeping solution contains fromabout 1-25%, preferably 5-15% of chlorhexidine. Accordingly, the choiceof solvent depends on the form of chlorhexidine being coated and on thetemperature contemplated for the steeping solution. Suitable solvents toserve as the steeping medium for chlorhexidine base are water, methylenechloride and preferably, methanol. For chlorhexidine salts, such as thehydrochloride, acetate, or preferably the gluconate, suitable solventsare methanol, ethanol and preferably water.

Steeping may be carried out for about 2 minutes to 2 hours at atemperature of about 15° to 60° C. In general, it has been found thatsteeping for about 15-30 minutes at about 50° C. gives asurface-permeated coating of chlorhexidine sufficient to provideanti-infective protection for vascular or other catheterization of about1-14 days. It is, of course, evident that a chlorhexidine coating may beformed on either or both the outside and lumen walls of the cathetermerely by contacting the desired walls with the steeping solution. Thus,steeping solution may be drawn into the lumen for contact with the lumenwall only, or the lumen may be filled with a solid rod so that thesteeping solution contacts only the outside wall.

Another embodiment of the invention is a laminated catheter whichincludes a base polymer having coated thereon a polymeric layercontaining bulk distributed chlorhexidine. Polymers suitable for use asthe laminated polymeric layer may be the same polymers having a waterabsorption of 0.6 to 6.0% by weight as disclosed above for catheterfabrication. If desired, chlorhexidine may also be bulk distributed inthe base polymer. The laminated catheter of this embodiment of theinvention may be prepared by coextrusion of polymer melts containingbulk distributed chlorhexidine prepared as described above. For example,the coextrusion unit disclosed in U.S. Pat. No. 4,581,390 to Flynn, maybe used. A catheter having laminated polymeric layers on both sides ofthe base layer may be prepared by simultaneous extrusion of three layersthrough a suitable tri-layer die. Such a tri layer tubing may have bulkdistributed chlorhexidine in any one, two or all three of the layers,which may be of different thickness, or, if desired, a different agentmay be either bulk distributed or surface coated onto one or both of thelaminated layers.

Alternatively, the laminated catheter of the invention may be preparedby a coating process. For example, a thermoplastic polyurethar andchlorhexidine acetate may be dissolved in a solvent such asdimethylacetamide, toluene, pertoleum ether, tetrahydrofuran,methylenechloride, dimethylformamide, N-methylpyrrolidone or mixturesthereof. The article of base polymer, with or without bulk distributedchlorhexidine, may then be dipped into the solution to coat the articlewith the laminating layer. It is evident that the dipping process mayprovide a laminating layer on both the outer and lumen surfaces of thearticle, or if desired, the laminating layer may be applied to only theouter surface or only the lumen surface.

The preferred catheter of the invention includes a polymer having bothbulk distributed chlorhexidine and a chlorhexidine coating. Thisembodiment of the invention produces a dual anti-infective activity. Thesurface coating provides a readily available and rapid release ofchlorhexidine. The bulk distributed chlorhexidine, due to thehydrophilic nature of the polymer, migrates slowly to the surface whenthe catheter is in contact with a body fluid and produces anti-infectiveactivity of long duration.

For some applications of the anti-infective article of the invention, itmay be desirable to include an antithrombogenic agent. Thus, anotherpreferred article has chlorhexidine bulk distributed in the polymer andan antithrombogenic agent, such as dextran sulfate or, preferablyheparin, coated thereon. A suitable method for ionically affixingheparin is that of Grode et al. (Journal of Biomedical MaterialsResearch Symposium, 3, 77 (1972)) wherein a quaternary ammonium surfaceactive agent such as, for example, tridodecylmethylammonium chloride, ispermeated into the surface of the polymer and then reacted with sodiumheparin. Another suitable method is that of Solomon et al. (U.S. Pat.No. 4,521,564) in which heparin is covalently attached to a polymericsurface containing an amino group.

Although the invention has heretofore been described in terms of thepreferred chlorhexidine, the use of other anti-infective agents mayconfer desirable properties on the catheter of the invention. Forexample, an article having bulk distributed chlorhexidine may be surfacecoated with an antibiotic. Preparation of such an article may be carriedout by permeating the polymer with a quaternary ammonium salt, asdescribed above, and reacting the salt thereby affixed to the polymersurface with the desired antibiotic. Exemplary of antibiotics which aresuitable for affixation to the article of the invention are penicillin,oxacillin, clindamycin, carbenicillin, cephalosporins, cefoxitin,cefazolin, dicloxacillin, cloxacillin and clavulanic acid and mixturesthereof.

The anti-infective catheter prepared by the method of the invention willnow be described in more detail with the aid of the drawings. In thefollowing discussion of the drawings, elements identical orsubstantially similar to previously described elements are given thesame reference number with a letter suffix. FIG. 1 shows polymericcatheter tubing 10 having an outside wall 12, a lumen 14 and a lumenwall 16. FIG. 2 shows tubing 10 having chlorhexidine molecules 18permeated by steeping into the surface of outside wall 12, and FIG. 3slows chlorhexidine molecules 18 permeated into the surface of lumenwall 16.

FIG. 4 shows polymeric tubing 10a having an outside wall portion 12a, alumen 14a and a lumen wall 16a. Chlorhexidine molecules 20 are bulkdistributed throughout the polymer.

FIG. 5 illustrates a preferred catheter 10b of the invention. Catheter10b has an outside wall 12b, a lumen 14b and a lumen wall 16b. Permeatedinto the surfaces of walls 12b and 16b are chlorhexidine molecules 18b.Chlorhexidine molecules 20b are bulk distributed in the catheter.

Laminated anti infective catheters in accordance with the invention areillustrated in FIGS. 6-9. In FIGS. 6 and 7, catheter 21 includes a basepolymeric tubing 22 having an outside wall portion 24, a lumen 26 and alumen wall 28. A polymeric laminating layer 30 having a surface 32 iscoated onto base tubing 22. Chlorhexidine molecules 20c are bulkdistributed in layers 22 and 30 and chlorhexidine molecules 18c arepermeated into the surface of layer 30.

FIG. 8 illustrates a laminated catheter tubing having chlorhexidinemolecules 20d bulk distributed in outer polymeric layer 30d andantibiotic molecules 36, indicated by the letter A permeated into theoutside and lumen surfaces.

A laminated catheter tubing illustrated in FIG. 9 has bulk distributedchlorhexidine molecules 20e in the inner base layer 22e and bulkdistributed molecules of silver sulfadiazine 38, indicated by the letterS in the laminating layer 30e.

A catheter tubing having laminated layers on both the outside and lumensurfaces is illustrated in FIG. 10. Base polymeric layer 22f haslaminated polyurethane layer 30f coated onto both the lumen wall and theoutside wall surfaces of base layer 22f. Chlorhexidine molecules 20f arebulk distributed in the laminated layers.

The following examples are provided to further illustrate typicalcatheter preparations of the invention and both in vitro and in vivoprocedures for determining their anti-infective properties.

EXAMPLE I Preparation of Polyurethane Tubing Having Bulk DistributedChlorhexidine Diacetate

Polyurethane pellets were blended with 5% chlorhexidine diacetate powderwith the Werner and Pfleiderer, Model ZDSK-28 twin screw compounder andthe well blended mixture was extruded into 16 gauge tubing using aKillion one inch extruder at approximately 175° C.

EXAMPLE II Test for Anti Infective Activity, (In Vitro)

In vitro antimicrobial activity of the anti-infective tubing of theinvention was measured by a standard zone of inhibition test. A broth ofthe test organism, such as S. aureus, was started from standard disks(Bactrol) in trypticase soy broth (TSB) and allowed to grow overnight. A0.2 ml aliquot of the overnight broth was transferred to a freshsolution of TSB and allowed to grow for 2 to 5 hours until the turbidityof the solution was equivalent to a 1% barium sulfate standard solution.A 0.2 ml aliquot of this broth was transferred to a Mueller-Hinton (M-H)agar plate and spread evenly on the surface. Medical tubings of theinvention were cut into suitable lengths of 1.5 cm and embedded into thesurface of the agar. The plates were then cultured 16 hours (overnight).Plates were evaluated for the inhibition of bacterial growth visually bythe unaided eye. Zones were measured in millimeters across the axis ofthe tubing, the measurement including the diameter of the medicalarticle.

Tubing prepared as described in Example I above demonstrated thefollowing antimicrobial activity in vitro.

    ______________________________________                                        Organism       Zone, mm                                                       ______________________________________                                        S. aureus       8.3 ± 1.3                                                  S. epidermidis 12.3 ± 0.5                                                  C. albicans    12.8 ± 0.5                                                  ______________________________________                                    

Permanency of the chlorhexidine was evaluated using a saline leachstudy. The tubings of Example I were exposed to 37° C. normal saline forvarious lengths of time. At the appropriate time interval, samples wereretrieved from the saline and placed on a prepared agar plate asdescribed above. Zone sizes were measured as above to determine retainedantimicrobial activity. The following results were obtained:

    ______________________________________                                                       Zone of Inhibition,                                            Leach Time, hrs.                                                                             S. aureus, mm.                                                 ______________________________________                                        0              11.3 ± 1.3                                                  1              10.7 ± 1.2                                                  4              9.3 ± 1.2                                                   8              8.7 ± 0.6                                                   24             7.7 ± 1.5                                                   ______________________________________                                    

EXAMPLE III Preparation of Polyurethane Tubing Having Bulk DistributedChlorhexidine Dihydrochloride

Polyurethane pellets were blended with either 4.0, 6.0 or 8.0 percentchlorhexidine dihydrochloride via the twin screw compounder. The blendedmaterial was then extruded into tubing and evaluated for in vitroantimicrobial activity against S. aureus using the zone of inhibitionmethod described in Example II. The following results were obtained:

    ______________________________________                                        Tubing, % Chlorhexidine                                                                          Zone, min.                                                 ______________________________________                                        4.0                4.7 ± 0.6                                               6.0                6.0 ± 0.0                                               8.0                3.0 ± 1.0                                               ______________________________________                                    

EXAMPLE IV Preparation of Polyurethane Tubing Having Both BulkDistributed and Surface Permeated Chlorhexidine

Polyurethane polymer pellets and 3% chlorhexidine dihydrochloride werefirst blended via a twin screw compounder at approximately 200° C. Theblended material was then extruded using standard tubing extrusionequipment at a temperature of approximately 175° C. A surface coating ofchlorhexidine was provided by steeping the polyurethane tubing in a 10%aqueous solution of chlorhexidine digluconate for 15 minutes at 50° C.The finished tubing produced the following zone of inhibition resultswhen evaluated according to Example II.

    ______________________________________                                        Organism      Zone, mm                                                        ______________________________________                                        S. aureus     15.0 ± 1.0                                                   C. albicans   5.8 ± 3.6                                                    ______________________________________                                    

EXAMPLE V In Vivo Test for Anti Infective Activity

The antimicrobial containing tubings of Example I were evaluated forefficacy in vivo with a subcutaneous rabbit model. Sterile tubingsamples were placed in a surgically created pocket on the shaved back ofa rabbit which had been washed and cleaned with an antiseptic. Thetubing was sutured in place to prevent the rabbit from removing it. A1×10³ inoculum of Staphylococcus aureus colony forming units (CFU) wasinjected into the subcutaneous pocket at the time of tubing insertion toinitiate the test. Tubing samples were then retrieved from the rabbitover a period of days. Recovered samples were then quantitativelyanalyzed for the amount of S. aureus present using the method of Solomonand Sherertz, J. Controlled Release, 6 (1987) 343-352. Non treatedtubing samples were run concurrently as controls. The following resultswere obtained:

    ______________________________________                                                log CFU, indwelling time                                              Tubing    4 days       7 days    14 days                                      ______________________________________                                        Control   2.37 ± 2.99                                                                             3.17 ± 3.48                                                                          3.44 ± 3.83                               Example I 0.01 ± 0.00                                                                             0.72 ± 1.49                                                                          1.10 ± 1.48                               ______________________________________                                    

EXAMPLE VI Preparation of Laminated Polyurethane Tubing Having BulkDistributed Chlorhexidine in Both Layers

Polyurethane and polyurethaneurea polymer resins were separatelyprocessed through the twin screw compounder with 4% and 6% chlorhexidinehydrochloride respectively as described in Example IV, resulting in bulkdistributed chlorhexidine in both polymers. The antimicrobial containingresins were then coextruded into tubing using standard equipment. Theresulting tubing exhibited the following rates of release (determined asin Example II) of chlorhexidine from the internal and external tubingsurfaces which are proportional to the resin's chlorhexidine content.

    ______________________________________                                                   Release Rate, mm. of zone                                          Hours        4%         6%                                                    ______________________________________                                        0            4.0        6.5                                                   1            2.7        5.8                                                   2            2.3        3.8                                                   ______________________________________                                    

EXAMPLE VII Preparation of Laminated Polyurethane Tubing Having BulkDistributed Chlorhexidine in the Outer Layer Only

Polyurethane polymer pellets and 5% chlorhexidine dihydrochloride werefirst blended via the twin screw compounder as described in Example IV.The antimicrobial-containing resin was then coextruded along with a nonantimicrobial containing resin such that the lumen surface of the tubingdid not contain any antimicrobial. The outer tubing layer thus providedantimicrobial activity to prevent or reduce microbial migration throughthe catheter wound tunnel, while the inner lumen was chlorhexidine free,thereby eliminating potentially adverse reactions such as intravenousinfusion (drug) chlorhexidine interactions.

EXAMPLE VIII Preparation of Polyurethane Tubing Having Both BulkDistributed Chlorhexidine and Heparinized Surfaces

Polyurethane polymer pellets and 6% chlorhexidine dihydrochloride werefirst blended via a twin screw compounder as described in Example IV.Bulk distributed antimicrobial tubing was then extruded into 16 gaugetubing using standard equipment. The tubing was then treated accordingto the method of Grode et al. (supra) using tridodecyl(methylammoniumchloride) to provide an ionically bonded heparin coating to both theinner and outer tubing surfaces, thus yielding a catheter tube with bothantimicrobial and antithrombogenic properties. The tubing produced thefollowing in vitro antimicrobial effects.

    ______________________________________                                        Organism    Zone of Inhibition, mm                                            ______________________________________                                        S. aureus   3.5 ± 0.6                                                      C. albicans 6.3 ± 1.2                                                      ______________________________________                                    

The tubing also demonstrated antithrombogenic efficacy as shown by apartial thromboplastin time of greater than 1800 seconds extension whendetermined by the procedure of B. A. Brown, Hematology Principles andProcedures, Third Edition, Lea and Fabiger, Co., 1980.

EXAMPLE IX Preparation of Polyurethane Tubing Having Both BulkDistributed Chlorhexidine and a Surface Layer of Covalently BoundHeparin

Polyurethane polymer pellets and 5% chlorhexidine diacetate were blendedwith the twin screw compounder and extruded into tubing as described inExample VIII. The tubing was then treated to provide a covalently bondedlayer of heparin to both the inner and outer lumen surfaces using themethod of Solomon et al., supra. This tubing demonstrated bothantimicrobial and antithrombogenic properties similar to the tubing ofExample VIII.

EXAMPLE X Preparation of Polyurethane Tubing Having Both BulkDistributed Chlorhexidine and Surface Bound Antibiotic

Polyurethane polymer pellets and 5% chlorhexidine dihydrochloride wereblended with the twin screw compounder and extruded into tubing asdescribed in Example VIII. The tubing was then coated with ionicallybonded dicloxicillin by the method of Solomon and Sherertz (supra) toboth the inner and outer tubing surfaces. The resulting tubing had abulk distributed broad spectrum antimicrobial (chlorhexidine) and anarrow layer of antibiotic with specific activity on the tubing surface.Other antibiotics specifically targeted for specific organisms may beused.

EXAMPLE XI Preparation of Laminated Polyurethane Tubing with BulkDistributed Chlorhexidine and Surface Bound Antibiotic

Polyurethane tubing was prepared as described in Example VII with bulkdistributed chlorhexidine in the outer tubing layer. Following tubingextrusion, the tubing was treated as described in Example X to providean ionically bonded dicloxicillin coating to both the inner and outertubing surfaces. This produced a tubing which had specific and broadantimicrobial action but without the presence of chlorhexidine in directcontact with the infusion fluid path.

EXAMPLE XII Preparation of a Laminated Polyurethane Tubing with NoExterior Surface Distributed Chlorhexidine and with Surface BoundAntibiotic

Polyurethane polymer pellets were bulk distributed with 5% chlorhexidinedihydrochloride by twin screw compounding. The melt was coextruded withresin containing no antimicrobial as described in Example VII, resultingin an inner layer with chlorhexidine, and an outer tubing layer with nochlorhexidine. Following extrusion, the tubing was treated as describedin Example X to provide an ionically bonded clindamycin coating to boththe inner and outer tubing surfaces.

EXAMPLE XIII Preparation of Laminated Polyurethane Tubing Having BulkDistributed Chlorhexidine and Silver Sulfadiazine

A. Polyurethane polymer pellets and 5% chlorhexidine dihydrochloridewere compounded via twin screw processing. Additional polyurethanepellets were compounded with 2% silver sulfadiazine. The two compoundedresins were then coextruded into tubing such that the inner layercontained bulk distributed chlorhexidine, and the outer layer containedbulk distributed silver sulfadiazine. This tubing had one type ofantimicrobial present on the outer surface, and a differentantimicrobial present on the inner surface.

B. Polyurethane resins were prepared as in A and coextruded into tubingsuch that the inner layer contained bulk distributed silver sulfadiazineand the outer layer contained bulk distributed chlorhexidine.

EXAMPLE XIV Preparation of Laminated Polyurethane Having BulkDistributed Chlorhexidine Dihydrochloride But No Surface Layer ofChlorhexidine

A melt of polyurethane pellets and 5% chlorhexidine dihydrochloride wasprepared by twin screw compounding and triextruded with resin withoutantimicrobial to give antimicrobial tubing sandwiched between two nonantimicrobial layers.

EXAMPLE XV Comparison of the Flexibility of Polyolefins and UrethanePolymers

In accordance with the procedure of Zdrahala et al. (Polyurethanes inBiomedical Engineering, II, H. Planck et al., ed., Elsevier SciencePublishers B. V. Amsterdam 1987, p 1-18), pieces of 16 gaugepolyurethane (65D) and polypropylene tubing were tested for the effectof absorbed water on tubing stiffness on the Instron Model 1122Universal Testing Machine. Bending forces in grams were determined after24 hours under ambient conditions of 23° C. and 50% relative humidityand after soaking in normal saline for 24 hours at 23° C. The followingresults were obtained:

    ______________________________________                                                       Bending Force, gr                                                             ambient                                                                              soak                                                    ______________________________________                                        polypropylene    331      368                                                 polyurethane     224       84                                                 ______________________________________                                    

It is seen that a 24 hour soak had substantially no effect on thestiffness of the polypropylene tubing, but reduced the stiffness of thepolyurethane by 62%.

Thus, the invention provides an anti-infective medical articlefabricated from a high melting hydrophilic polymer having up to 10% of achlorhexidine salt bulk distributed throughout the polymer. A preferredmethod to prepare the article includes blending of the polymer and thesalt by twin screw compounding and extruding at high temperature.

What is claimed is:
 1. A method for preparing a medical articlecomprising:a. extruding a first polymer having a water absorption of atleast 0.6% by weight to obtain a shaped first polymer. b. applying alaminated layer comprising a second polymer having a water absorption ofat least 0.6% by weight and an antiinfective agent selected from thegroup consisting of a biguanide and silver sulfadiazine bulk distributedtherein onto a surface of said shaped first polymer.
 2. The method ofclaim 1 wherein said biguanide is chlorhexidine.
 3. The method inaccordance with claim 2 wherein said chlorhexidine is selected from thegroup consisting of chlorhexidine base and a salt thereof.
 4. The methodin accordance with claim 3 wherein said salt of chlorhexidine isselected from the group consisting of the hydrochloride, acetate andgluconate.
 5. The method in accordance with claim 1 wherein said firstand second polymers are selected from the group consisting ofpolyurethane, polyurethaneurea and siloxane-urethane block copolymer. 6.The method of claim 1 further comprising preparing a melt of said secondpolymer and said anti-infective agent by twin screw compounding andperforming said applying step by dipping said shaped first polymer intosaid melt.
 7. The method of claim 1 wherein said preparing step includespreparing a melt of said first polymer and said applying step includespreparing a homogeneous melt of said second polymer and saidanti-infective agent and coextruding said melts.
 8. The method of claim1 further comprising preparing a solvent solution of said second polymerand said anti-infective agent and performing said applying step bydipping said shaped article into said solution.
 9. The method inaccordance with claim 1 further comprising permeating a quaternaryammonium salt into said laminated layer and reacting the permeated saltwith a material selected from the group consisting of an antibiotic andan antithrombogenic agent.